Over the years, certain drugs have been sold in compositions suitable for pulmonary delivery to treat various conditions in humans. Such pulmonary drug delivery compositions include an aerosolized drug formulation that is inhaled by the patient so that the active agent can reach the alveolar region of the lungs.
Pulmonary drug delivery can be achieved by, for example, delivery of dry powder formulations to the deep lung. These powders have been prepared by spray drying as described in WO 96/32149, WO 99/16419 and U.S. Pat. Nos. 5,976,574, 5,985,248, 6,001,336, and 6,051,256, the disclosures of which are incorporated herein in their entirety. Preparing pharmaceutical compositions as stable dry powders by spray drying, however, poses many challenges. In order to scale up the spray drying process, it is desirable to increase the total solids content of the feed stream. It was found, however, that the emitted dose of powders prepared from higher total solids content feed streams, that is above about 1% (w/v), declined significantly.
In addition, the ability to deliver pharmaceutical compositions as dry powders poses many challenges. For example, particles containing both crystalline and amorphous phases may exhibit physical or chemical instability. Transformations of the materials during storage from amorphous to crystalline may result in such instability as a result of particle fusion and other physical changes. Further, crystallization tends to increase the water content in the remaining amorphous phase and thereby decrease the glass transition temperature (Tg) of the materials. Increased water content of the amorphous region increases molecular mobility and may increase chemical degradation reaction rates (i.e., hydrolysis, aggregation, etc.). Formulations having a higher percentage of crystallinity are less likely to degrade during storage.
It is known to provide spray dryers with drying zones which are maintained at different temperatures in order to provide some control of the drying kinetics. For example, U.S. Pat. No. 4,257,799 discloses a method for producing small hollow glass spheres having an outer diameter from about 100 to 500 microns wherein the method involves introducing aqueous droplets of a glass-forming solution into a long vertical drop oven or furnace having varying temperature regions.
U.S. Pat. Nos. 5,632,100, 5,924,216 and 4,281,024 also disclose spray drying with multiple drying zones, in which larger particles are typically subjected to a secondary drying in order to achieve desired moisture content.
U.S. Pat. No. 6,051,257 discloses structurally modifying particles after they are formed by a spray drying process in order to impart desired physical properties to the particles. The particle modifier is typically a furnace having temperature control independent of the spray dryer furnace and is positioned to receive the formed particles after they exit the spray dryer furnace.
U.S. Pat. No. 5,874,063 to Briggner et al. describes a method for increasing the crystallinity of conventional fine particles by treating the already manufactured fine particles with a solvent in the vapor phase and then removing the excess solvent. The solvent may be an organic solvent or it may be water.
WO 00/64552 discloses a method of spray drying and a plant therefore whereby spray drying is performed at increased pressure. The invention is directed to spray drying where an amorphous product is desired and/or where a high bulk density powder is desired. Spray drying according to this disclosure is conducted in a pressurized environment not below 1.25 bar absolute.
There remains a need to provide control of drying kinetics of spray drying processes in order to produce particles of desired physical properties for pharmaceutical applications such as the preparation of dry powders for inhalation. It is desirable to provide systems and methods which provide for dry powders with acceptable pulmonary delivery characteristics. The present invention overcomes the above shortcomings in the prior art.